Molecular Mechanisms of Endocrine-Disrupting Chemicals and Emerging-Pollutant Toxicity in Human Reproduction: From Xenobiotic Exposure to Fertility Impairment and Reproductive Carcinogenesis
Abstract
Human fertility is declining across industrialised populations, while the incidence of hormone-dependent reproductive cancers rises. Endocrine-disrupting chemicals (EDCs) and structurally related emerging pollutants are implicated in both. These two outcomes are generally reviewed as separate studies. This review argues that they are two latencies of a single molecular toxicology. The compounds concerned are structurally diverse: phthalates, bisphenols, per- and polyfluoroalkyl substances (PFASs), pesticides, polychlorinated biphenyls (PCBs) and dioxins, brominated and organophosphate flame retardants, pharmaceuticals and personal-care products (PPCPs), and micro- and nanoplastics. They nonetheless converge on a limited repertoire of molecular lesions. These include the disruption of hypothalamic-pituitary-gonadal (HPG) signalling through kisspeptin/GnRH and gonadotropin gene expression and interference at nuclear and membrane hormone receptors (ERα/β, AR, GPER, thyroid receptors, AhR, PPARγ). They also include the inhibition of steroidogenesis at StAR and the CYP11A1-CYP17A1-CYP19A1/3β-HSD/17β-HSD cascade and reactive-oxygen-species generation with mitochondrial dysfunction and Keap1-Nrf2 disruption. Epigenetic reprogramming through DNA methylation, histone modification and non-coding RNAs, together with crosstalk with metabolic and immune signalling, completes the set. These lesions produce measurable cytotoxic and genotoxic damage to gametes and the early embryo: sperm…
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